Prostaglandin E.sub.2 (abbreviated as PGE.sub.2 hereafter) has been known as a metabolite in the arachidonate cascade. Its known activities include cyto-protective activity, uterine contractile activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity etc. In recent study, it was found that PGE2 receptor was divided into some subtypes which possess different physiological role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3 and EP4 (Negishi M. et al, J. Lipid Mediators Cell Signalling 12, 379-391 (1995) ).
The present inventors investigated to find compounds which bind to each receptor specifically; we found that the compounds of the present invention could bind strongly to EP4 subtype receptor and then achieved the present invention.
The compound of formula (I) possess a binding activity for EP4 subtype receptor strongly. Therefore they are useful for the treatment and/or prevention of immunologic diseases (autoimmune diseases, immunological deficiency diseases, organ transplantation etc.), asthma, abnormal bone formation, neuronal cell death, liver damage, nephritis, hypertension, myocardiac ischemia etc.
Among the compounds of the present invention of the formula (I), compounds which bind weakly to receptor subtypes except for EP4 receptors do not express other effects and therefore it is thought that such compounds will be a medical agent which have less side-effects.
On the other hand, many modified PGs wherein 7th position carbon atom is replaced by sulfur atom are known. The following application is mentioned for an example.
In the specification of Japanese Kokai No. 57-108065 (i.e. EP 51284), the following compounds are disclosed as an agent for anti-platelets aggregation.
I.e. 7-thiaprostaglandin derivatives of the formula (A): ##STR3## (wherein R.sup.1A is hydrogen atom, lower alkyl or pharmaceutically acceptable cation,
In the specification of Japanese Kokai No. 58-148857, the following compounds are disclosed as an agent for anti-platelet aggregation.
I.e. 7-thiaprostaglandin derivatives of the formula (B): ##STR4## (wherein R.sup.1B is hydrogen atom or C1-10 alkyl, 5-6 membered alicyclic ring or phenyl,
In the specification of Japanese Kokai No. 58-110562, it is disclosed that the following compounds are useful for controlling vascular action.
I.e. 7-thiaprostaglandin derivatives of the formula (C): ##STR5## (wherein G is --COOR.sup.8C, --CONR.sup.9C R.sup.10C or --CH.sub.2 OR.sup.11C,
In the prior arts described compounds of the formula (A) and (B), these compounds wherein the 7th carbon atom are replaced by a sulfur atom are hard to be metabolized and are useful for anti-aggregation. In the prior art concerning compounds of the formula (C), these compounds are useful for controlling vascular action.